[Early determinants of chronic obstructive pulmonary disease: Lung regeneration, a new therapeutic target?] / Déterminants précoces de la bronchopneumopathie chronique obstructive : la régénération pulmonaire, une nouvelle piste thérapeutique ?

Chronic obstructive pulmonary disease, a disease of increasing incidence, is related mainly to smoking. Although symptoms only appear at adulthood, the disease can develop from early life events. For example, bronchopulmonary dysplasia, which occurs in preterm infants, is characterized by airspace enlargement and could lead to late lung consequences. Once the lesions are established, no curative treatment is available. Stimulating lung regeneration from endogenous stem cells is therefore an exciting research domain, particularly through the activation of the mesenchymal contingent located in the lung stem cell niche.

[Cellular senescence and pulmonary disease: COPD as an example]. / Sénescence cellulaire et pathologies pulmonaires: exemple de la BPCO.

The biological mechanisms of aging, and more specifically cellular senescence, are increasingly a subject of research. Cellular senescence may be a common determinant of many age-related diseases, including some chronic lung diseases such as chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis. Many arguments suggest that these diseases are associated with premature senescence of lung cells, which may be involved in the pathophysiology of respiratory alterations. Furthermore, these diseases are associated with systemic manifestations, such as bone loss, muscle wasting and atherosclerosis, which impact on symptoms and prognosis. Whether these alterations are related to a common pathogenic mechanism or develop independently in patients with COPD remains an open question. In this review, we will focus on cellular senescence and COPD. Two concepts will be discussed: (1) the role of cell senescence in the pathophysiology of lung destruction, vascular remodeling and inflammation in COPD, (2) the possible link between the pulmonary and systemic manifestations of COPD which could reflect a general process of accelerated aging.

Interaction of matrix metalloproteinases with pulmonary pollutants.

An air pollutant consists of any atmospheric substance that may harm humans, animals, vegetation or material. Various air pollutants have been reported, differing in their physicochemical characteristics. They can be grouped into four categories: gaseous pollutants (e.g. ozone, sulfur dioxide, oxides of nitrogen, carbon monoxide and volatile organic compounds), persistent organic pollutants, heavy metals (e.g. cadmium, lead and mercury) and particulate matter (coarse, fine and ultrafine). These pollutants can reach the respiratory system, eliciting pulmonary and/or systemic effects. These effects include inflammation, tissue remodelling and carcinogenesis: all phenomena where matrix metalloproteases (MMPs) play critical roles, given their broad effects on matrix remodelling and modulation of inflammation and cell signalling. Moreover, since expression and activity of MMPs can be induced by such stimuli, the hypothesis has been raised that MMPs could be involved in the health effects of pollutants. Until now, the implication of MMPs in these effects has been studied only for some pollutants and for a restricted selection of MMPs (mainly MMP-1, -2, -9 and -12), while evidence for a link between MMP induction/activation and health effects remains scarce. A larger number of studies is, therefore, needed in order to better understand the implication of MMPs in health effects associated with air pollution.

Respiratory effects of manufactured nanoparticles.

Nanotechnology is the set of techniques used to engineer, characterize, and produce materials that have at least one dimension within the nanoscale. These nanomaterials, or nanoobjects, include nanoparticles and nanotubes. As dictated by the laws of quantum physics, a size within the nanoscale results in unique physicochemical properties and distinctive behaviors. Nanotechnology has a host of applications in fields ranging from cosmetology to the industry and medicine. The production and use of nanomaterials are expanding at a brisk pace. However, concerns are emerging about the potential health effects of nanoparticles in the short and long terms. These concerns are rooted in data on the harmful health effects of micrometric airborne particulate matter. Conceivably, these adverse effects might be amplified when the particles are within the nanoscale. This article is a nonexhaustive overview of current data on the penetration, deposition, translocation, and elimination of inhaled nanoparticles and on the respiratory effects of metallic nanoparticles (with special attention to titanium dioxide) and carbon nanotubes. Both in vivo and in vitro studies consistently found biological effects of nanoparticles on the respiratory system, including oxidative stress generation, proinflammatory and prothrombotic effects, pulmonary fibrosis and emphysema, and DNA damage. Improved knowledge of the potential biological effects of nanoparticles is needed to guide preventive strategies for the workplace and/or general population if needed.

NRF2 targeting: a promising therapeutic strategy in chronic obstructive pulmonary disease.

Several convergent destructive mechanisms such as oxidative stress, alveolar cell apoptosis, extracellular matrix proteolysis and chronic inflammation contribute to chronic obstructive pulmonary disease (COPD) development. Evidence suggests that oxidative stress contributes to the pathophysiology of COPD, particularly during exacerbations. Nuclear factor erythroid-2-related factor 2 (NRF2), a transcription factor expressed predominantly in epithelium and alveolar macrophages, has an essential protective role in the lungs through the activation of antioxidant response element-regulated antioxidant and cytoprotective genes. Animal models and human studies have identified NRF2 and several NRF2 target genes as a protective system against inflammation and oxidative stress from cigarette smoke, a major causative factor in COPD development. Hence, NRF2 targeting might provide clinical benefit by reducing both oxidative stress and inflammation in COPD.

Oxidative stress targets in pulmonary emphysema: focus on the Nrf2 pathway.

IMPORTANCE OF THE FIELD: Oxidative stress has been implicated in the pathogenesis of pulmonary emphysema. Nuclear factor erythroid-2-related factor 2 (Nrf2) a major antioxidant transcription factor could play a protective role in pulmonary emphysema. AREAS COVERED IN THIS REVIEW: Nrf2 is ubiquitously expressed throughout the lung, but is predominantly found in epithelium and alveolar macrophages. Evidence suggests that Nrf2 and several Nrf2 downstream genes have an essential protective role in the lung against oxidative stress from environmental pollutants and toxicants such as cigarette smoke, a major causative factor for the development and progression of pulmonary emphysema. Application of Nrf2-deficient mice identified an extensive range of protective roles for Nrf2 against the pathogenesis of pulmonary emphysema. Therefore, Nrf2 promises to be an attractive therapeutic target for intervention and prevention strategies. WHAT THE READER WILL GAIN: In this review, we discuss recent findings on the association of oxidative stress with pulmonary emphysema. We also address the mechanisms of Nrf2 lung protection against oxidative stress based on emerging evidence from experimental oxidative disease models and human studie. TAKE HOME MESSAGE: The current literature suggests that among oxidative stress targets, Nrf2 is a valuable therapeutic target in pulmonary emphysema.

Prolonged cigarette smoke exposure decreases heme oxygenase-1 and alters Nrf2 and Bach1 expression in human macrophages: roles of the MAP kinases ERK(1/2) and JNK.

Tobacco may be involved in the decreased macrophage heme oxygenase-1 (HO-1) expression described in smoking-induced severe emphysema, via the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-BTB and CNC homology 1, basic leucine zipper transcription factor 1 (Bach1) pathway. We assessed in vitro effects of cigarette smoke condensate (CS) in the human monocyte/macrophage cell line (THP-1). CS exposure led to increased HO-1 and nuclear Nrf2 expression (6 h) followed by decreased HO-1 expression concomitantly with nuclear Nrf2/Bach1 ratio decrease (72h). CS-induced mitogen-activated protein kinase (MAPK) phosphorylation. Extracellular-signal-regulated kinase(1/2) (ERK(1/2)) and c-Jun NH2-terminal kinase (JNK) inhibition completely abrogated CS effects on HO-1 expression and nuclear Nrf2/Bach1 translocation. These results suggest that ERK(1/2) and JNK are involved in CS-induced biphasic HO-1 expression by a specific regulation of Nrf2/Keap1-Bach1.

[Respiratory effects of manufactured nanoparticles]. / Effets respiratoires des nanoparticules manufacturées.

Nanotechnology, defined as techniques aimed to design, characterize and produce materials on a nanometer scale, is a fast-growing field today. Nanomaterials are made of nanoobjects (nanoparticles, nanofibers, nanotubes...). The nanoscale confers on these materials their novel, hitherto unknown, chemical and physical properties by the laws of quantum physics which are essentially expressed on this scale. Nanotechnology applications are numerous (e.g., cosmetics, industry and medicine) and they keep growing. We can safely predict that the production and utilization of nanomaterials will increase greatly in the years to come. Nonetheless, the same properties that make these nanomaterials very attractive are a source of concern: there are questions about their potential toxicity, their long-term side effects, and their biodegradability. These questions are based on knowledge of the toxic effects of micrometric particles in air pollution and the fear that these effects will be amplified because of the nanometric size of the new materials. We present in this article a global but not exhaustive summary of current knowledge. We begin by defining lung penetration, deposition, translocation and elimination of nanoparticles. Finally, we consider the respiratory effects of metallic nanoparticles, titanium dioxide nanoparticles in particular, and carbon nanotubes. In vivo and in vitro experimental studies currently available highlight the existence of biological effects of nanoparticles on the respiratory system with generation of oxidative stress, pro-inflammatory and pro-thrombotic effects and the possible development of fibrosis and pulmonary emphysema or DNA damage. A better understanding of the potential biological effects of nanoparticles is required to implement appropriate preventive measures in the workplace and/or in the general population, if this should be necessary.

[Characteristics of the patients included in the French cohort of patients with emphysema caused by alpha-1 antitrypsin deficiency]. / Caractéristiques des patients inclus dans la cohorte française de patients emphysémateux déficitaires en alpha-1 antitrypsine.

INTRODUCTION: Alpha-1 antitrypsin deficiency is associated with the occurrence of pulmonary emphysema. The aim of this study is to describe the characteristics of patients with alpha-1 antitrypsin deficiency associated pulmonary emphysema. METHODS: We describe a prospective cohort study including adult patients with alpha-1 antitrypsin deficiency associated pulmonary emphysema confirmed by CT scan living in France. Patients' clinical and functional characteristics, quality of life measures and management were recorded every 6 months during a five-year period. RESULTS: 201 patients were included from 56 centres between 2005 and 2008. The characteristics of 110 patients have been analysed. Mean age was 50 years (SD:11.8), 62.7% were males, 90% were tobacco smokers. The main functional results (% predicted) were: FEV1: 42.8 (19.6), CPT: 128.3 (21.7), CRF: 167.0 (46.0), 6 minute walking distance (meters): 413 (130). 51 (46.4%) patients received augmentation therapy. Augmentation therapy was administered weekly (37.5%), twice a month (35.4%) or monthly (25.5%). Study centre was the only factor associated with the likelihood to received augmentation therapy. CONCLUSIONS: The clinical and functional characteristics as well as management of these patients varied markedly. There is a need for a standardization of the management of patients with alpha-1 antitrypsin deficiency associated pulmonary emphysema.

[Contribution of ATP-dependent potassium channels, nitric oxide and prostaglandins in increase of diaphgram arteriolar blood fow during diaphgram contraction]. / Contribution des canaux potassiques ATP-dépendant, du monoxyde d'azote et des prostaglandines dans l'augmentation du débit artériolaire lors de la contraction du diaphragme.

ATP-sensitive potassium (K(ATP)) channels and nitric oxide (NO) have been suggested to contribute in mediating active hyperemia in diaphragm. However, no data is available in the current literature concerning their comparative contributions to arteriolar dilation during muscle contraction. The aim of this study was therefore to examine, by video microscopy in rats, the effects of superfusing the muscle with Krebs solution alone (group C), or Krebs solution containing either glybenclamide (3mdeltaM, a blocker of K(ATP), group GLY), or Nwdelta-nitro-L-arginine (300 mdeltaM, a NO synthase inhibitor, group NNA), or mefenamic acid (50 mdeltaM, a prostaglandin synthesis inhibitor, group MA) on second and third order of diaphragm (A2 and A3 respectively) arteriolar dilation elicited by 3 min muscle stimulation (40 Hz, train duration: 300 milliseconds, 90 cycles per min). In group C, A2 diameters increased by 67.5 +/- 1.9% referring to baseline at the end of the stimulation. This increase was significantly reduced in groups GLY and NNA (16.7 +/- 2.5% and 47.3 +/- 2.2% respectively, p < 0.001 as compared to group C) and was more important in group GLY than in group NNA (p < 0.001). By contrast, no difference in post-contraction diameter was observed between groups C and MA. Similar results were observed in A3 vessels. These results indicate that K(ATP) are more important mediators of functional diaphragm arteriolar dilation in rat than NO, whereas prostaglandins are not involved in this phenomenon.

Induction of apoptosis and absence of inflammation in rat lung after intratracheal instillation of multiwalled carbon nanotubes.

Several studies performed by intratracheal instillation showed that carbon nanotubes (CNT) induced pulmonary fibrosis, granulomas or inflammation. But, recently, two inhalation studies did not observed such pathological phenomena and suggest that granulomas could be due to the instillation of unbreathable agglomerates. In a previous study, we have described a simple method (using albumin as dispersing agent) which produced solutions containing more than 80% of agglomerate of breathable size. We report here results from intratracheal instillation of rats by 0, 1, 10 or 100 microg of MWCNT dispersed with albumin. After 1, 7, 30, 90, and 180 days, inflammation, apoptosis, fibrosis, respiratory parameters and granuloma formation were assessed. Results obtained by plethysmography, soluble collagen quantification, qRT-PCR and luminex measurement of cytokines expression and histopathological observation showed only evidence of apoptosis of alveolar macrophages. These result underline the importance of controlling MWCNT agglomerate size when exposing animals, through appropriate dispersion methods.

Dysregulation of elastin expression by fibroblasts in pulmonary emphysema: role of cellular retinoic acid binding protein 2.

BACKGROUND: All-trans retinoic acid (ATRA) stimulates elastin synthesis by lung fibroblasts and induces alveolar regeneration in animal models of pulmonary emphysema. However, ATRA treatment has had disappointing results in human emphysema. It was hypothesised that a defect in the ATRA signalling pathway contributes to the defect of alveolar repair in the human emphysematous lung. METHODS: Fibroblasts were cultured from the lung of 10 control subjects and eight patients with emphysema. Elastin and retinoic acid receptor (RAR)-beta mRNAs were measured in those cells in the presence of incremental concentrations of ATRA. RARs, retinoic X receptors (RXRs) and cellular retinoic acid binding protein (CRABP) 1 and 2 mRNAs were measured as well as CRABP2 protein content. The effect of CRABP2 silencing on elastin and RAR-beta expression in response to ATRA was measured in MRC5 lung fibroblasts. RESULTS: ATRA at 10(-9) M and 10(-8) M increased median elastin mRNA expression by 182% and 126% in control but not in emphysema fibroblasts. RAR-beta mRNA expression was induced by ATRA in control as well as emphysema fibroblasts. RARs, RXRs and CRABP1 mRNAs were similarly expressed in control and emphysema fibroblasts while CRABP2 mRNA and protein were lower in emphysema fibroblasts. CRABP2 silencing abrogated the induction of elastin but not RAR-beta expression by ATRA in MRC5 fibroblasts. CONCLUSION: Pulmonary emphysema fibroblasts fail to express elastin under ATRA stimulation. CRABP2, which is necessary for elastin induction by ATRA in MRC-5 cells, is expressed at low levels in emphysema fibroblasts. This alteration in the retinoic acid signalling pathway in lung fibroblasts may contribute to the defect of alveolar repair in human pulmonary emphysema. These results are the first demonstration of the involvement of CRABP2 in elastin expression.

Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema.

BACKGROUND: Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, plays a role in the pathophysiology of smoking-related pulmonary emphysema. Expression of several antioxidant proteins, such as heme oxygenase-1 (HO-1), glutathione peroxidase 2 (GPX2) and NAD(P)H:quinone oxidoreductase 1 (NQO1), results from an equilibrium created by positive or negative regulation by the transcription factors Nrf2, Keap1 and Bach1, respectively. However, whether the expression of these transcription factors is altered in emphysema and could account for decreased expression of antioxidant proteins is not known. A study was undertaken to investigate the expression and subcellular localisation of Nrf2, Keap1 and Bach1 as potential regulators of HO-1, GPX2 and NQO1 in alveolar macrophages, a key cell in oxidative stress, in lung surgical specimens from non-smokers without emphysema and smokers with and without emphysema. METHODS AND RESULTS: Western blot, immunohistochemical and laser scanning confocal analysis revealed that the Nrf2 protein level decreased significantly in whole lung tissue and alveolar macrophages (cytosol and nucleus) in patients with emphysema compared with those without emphysema. Conversely, Bach1 and Keap1 levels were increased in patients with emphysema. These modifications were associated with a parallel decrease in the expression of HO-1, GPX2 and NQO1 at the cellular level, which was inversely correlated with airway obstruction and distension indexes, and increased macrophage expression of the lipid peroxidation product 4-hydroxy-2-nonenal. Silencing RNA experiments in vitro in THP-1 cells were performed to confirm the cause-effect relation between the loss of Nrf2 and the decrease in HO-1, NQO1 and GPX2 expression. Nrf2/Keap1-Bach1 equilibrium was altered in alveolar macrophages in pulmonary emphysema, which points to a decreased stress response phenotype. CONCLUSIONS: This finding opens a new view of the pathophysiology of emphysema and could provide the basis for new therapeutic approaches based on preservation and/or restoration of such equilibrium.

Association of lung function decline with the heme oxygenase-1 gene promoter microsatellite polymorphism in a general population sample. Results from the European Community Respiratory Health Survey (ECRHS), France.

Inducible heme oxygenase (HO-1) acts against oxidants that are thought to play a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD), characterised by impaired lung function. A (GT)(n) repeat polymorphism in the HO-1 gene promoter can modulate the gene transcription in response to oxidative stress. We hypothesised that this polymorphism could be associated with the level of lung function and decline in subjects exposed to oxidative aggression (smokers). We genotyped 749 French subjects (20-44 years, 50% men, 40% never smokers) examined in both 1992 and 2000 as part of the ECRHS. Lung function was assessed by forced expiratory volume in 1 second (FEV1) and FEV1/forced ventilatory capacity (FVC) ratio. We compared long (L) allele carriers ((GT)(n) > or =33 repeats for one or two alleles) to non-carriers. Cross sectionally, in 2000, L allele carriers showed lower FEV1/FVC than non-carriers. During the 8 year period, the mean annual FEV1 and FEV1/FVC declines were -30.9 (31.1) ml/year and -1.8 (6.1) U/year, respectively. FEV1/FVC decline was steeper in L allele carriers than in non-carriers (-2.6 (5.5) v -1.5 (6.4), p = 0.07). There was a strong interaction between the L allele and smoking. In 2000, the L allele was associated with lower FEV(1) and FEV(1)/FVC in heavy smokers (> or =20 cigarettes/day) only (p for interaction = 0.07 and 0.002 respectively). Baseline heavy smokers carrying the L allele showed the steepest FEV1 decline (-62.0 (29.5 ml/year) and the steepest FEV1/FVC decline (-8.8 (5.4 U/year) (p for interaction = 0.009 and 0.0006). These results suggest that a long (L) HO-1 gene promoter in heavy smokers is associated with susceptibility to develop airway obstruction.

[Study of cellularity in bronchoalveolar fluid and bronchial reactivity to histamine in a model of asthma in guinea pig]. / Etude de la cellularité bronchoalvéolaire et de la réactivite des voies aériennes a l'histamine dans un modèle d'asthme chez le cobaye.

INTRODUCTION: Several studies showed that the guinea pig represents the animal of choice in the study of the asthma and more exactly in the study of the bronchial hyperreactivity. MATERIALS AND METHOD: In our model of asthma, guinea pigs were made sensitive with ovalbumine (OVA), a protein extracted from the white of egg, and provoked in a way repeated with aerosol challenge of OVA for the group OVA (1 challenge a day during six days). This group was compared with the group controls (C), animals injected with a salt solution (NaCl 0.9%) and receiving aerosol challenge of salt solution. The OVA group was subdivided into two groups: A studied group 6 hours after the aerosol challenge of OVA. A studied group 24 hours after the aerosol challenge of OVA. RESULTS: We showed an increasing increase of airway hyperresponsiveness to increasing doses of histamine in all groups of animals. This increase was significantly more important 6 hours after the last aerosol challenge of OVA (early airway hyperreactivity, OVA-6 group, n = 8) that at 24 hours after the last aerosol challenge (late airway hyperreactivity, OVA-24 group, n = 8). We had also noted a modification of cellularity in bronchoalveolar lavage fluid with an increase of the total number of cells essentially by increase of the rate of eosinophilia in OVA-6 group (n = 6) compared with OVA-24 group (n = 6) and Control group (n = 6). CONCLUSION: The model of bronchial hyperreactivity and modification of cellularity in guinea pig will allow us to envisage studies on the origin of differences of ability to react in the group OVA-6 and OVA-24 and to study the medicinal efficiency of plants used in Senegal in the treatment of the asthma.

Carbon monoxide reduces the expression and activity of matrix metalloproteinases 1 and 2 in alveolar epithelial cells.

Matrix metalloproteinases (MMPs), particularly MMP-1 and MMP-2, are involved in the pathophysiology of emphysema. MMPs contain zinc in the catalytic site and its expression is regulated transcriptionally via mitogen activated protein kinases (MAPKs). Carbon monoxide (CO), one of the end products of heme oxygenase activity, has anti-inflammatory properties, which are mediated, at least in part, by activation of p38 MAPK. Furthermore, CO has the unique ability to bind to metal centers in proteins and can affect their specific activity. Therefore, we hypothesized that CO could inhibit MMPs expression and/or activity. Here we show that a recently identified carbon monoxide-releasing molecule, [Ru(CO)3Cl2]2 (or CORM-2) inhibits MMP-1 and MMP-2 mRNA expression in the human lung epithelial cell line A549. The MMPs mRNA expression was unaffected by the p38 MAPK inhibitor SB203580, but in the case of MMP-1 was reversed by the antioxidant N-acetylcysteine. In addition, CORM-2 inhibited both MMP-1 and MMP-2 activities. Interestingly, no effect was observed with (Ru(DMSO)4Cl2), a negative control that does not contain CO groups. To the best of our knowledge this is the first evidence on the effect of CO on MMPs expression and activity. This effect could have important implications in the pathophysiology of emphysema and other diseases involving proteases/antiproteases imbalance.

[Diaphragmatic weakness in sepsis: the role of oxidant stress]. / Stress oxydant et diaphragme: rôle dans la défaillance contractile au cours du sepsis.

In sepsis contractile weakness of the diaphragm is a major cause of the onset of respiratory failure. This muscular weakness is the result of haemodynamic and metabolic disorders secondary to sepsis and also the damaging effects of inflammatory mediators, among which oxygen free radicals play a crucial role. This role is demonstrated by the protective effect of various exogenous anti-oxidants on diaphragmatic contraction. Early in the course of sepsis there is, in animal models and in man, an increased production of oxygen free radicals and nitric oxide (NO) in the diaphragm, principally within the mitochondria. The formation of peroxinitrite as the result of the action of NO on superoxide anions impairs mitochondrial respiration and consequently the energy production necessary for diaphragmatic contraction. Among the endogenous anti-oxidant systems haem oxygenase, which splits haemoglobin into bilirubin, iron and carbon monoxide, is an effective system for the protection of diaphragmatic function by limiting the damage of oxidant stress. Nevertheless a transient deficiency of local anti-oxidant defences during the early stages of sepsis, when the production of oxygen free radicals is intense, encourages the onset of contractile weakness.

Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling.

Airway inflammation and alterations in cellular turnover are histopathologic features of asthma. We show that the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear hormone receptor involved in cell activation, differentiation, proliferation, and/or apoptosis, is augmented in the bronchial submucosa, the airway epithelium, and the smooth muscle of steroid-untreated asthmatics, as compared with control subjects. This is associated with enhanced proliferation and apoptosis of airway epithelial and submucosal cells, as assessed by the immunodetection of the nuclear antigen Ki67, and of the cleaved form of caspase-3, respectively, and with signs of airway remodeling, including thickness of the subepithelial membrane (SBM) and collagen deposition. PPAR gamma expression in the epithelium correlates positively with SBM thickening and collagen deposition, whereas PPAR gamma expressing cells in the submucosa relate both to SBM thickening and to the number of proliferating cells. The intensity of PPAR gamma expression in the bronchial submucosa, the airway epithelium, and the smooth muscle is negatively related to FEV(1) values. Inhaled steroids alone, or associated with oral steroids, downregulate PPAR gamma expression in all the compartments, cell proliferation, SBM thickness, and collagen deposition, whereas they increase apoptotic cell numbers in the epithelium and the submucosa. Our findings have demonstrated that PPAR gamma (1) is a new indicator of airway inflammation and remodeling in asthma; (2) may be involved in extracellular matrix remodeling and submucosal cell proliferation; (3) is a target for steroid therapy.

Sepsis is associated with reciprocal expressional modifications of constitutive nitric oxide synthase (NOS) in human skeletal muscle: down-regulation of NOS1 and up-regulation of NOS3.

OBJECTIVE: To study the expression (mRNA and protein) and activity of the constitutive isoforms of nitric oxide synthase (NOS1 and NOS3) in a skeletal muscle of septic patients. DESIGN: Prospective study. SETTING: An adult trauma/surgical intensive care unit in an urban teaching hospital. PATIENTS: Sixteen septic patients and 21 controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Samples of the rectus abdominis muscle were obtained during surgical procedure. NOS mRNA, protein, and activity were detected by reverse-transcriptase polymerase chain reaction, Western blot, and the conversion of [3H]L-arginine to [3H]L-citrulline, respectively. The main results of this study are as follows: a) Levels of NOS1 mRNA and protein were significantly higher than those of NOS3 in the rectus abdominis muscle of control patients; b) NOS1 expression was down-regulated in septic patients, whereas NOS3 was up-regulated; c) these modulations were associated with a reduction in constitutive NOS activity; and d) modifications of NOS1 and NOS3 protein expression were correlated significantly with the severity of sepsis, assessed by the Simplified Acute Physiology Score II. CONCLUSIONS: Sepsis induces reciprocal expressional modifications of NOS1 and NOS3 in human skeletal muscle, which decreases muscular constitutive NOS activity. These modifications may have implications for muscle impairment in septic patients.